Drugs are often unable to reach the target site effectively and efficiently using conventional delivery systems, particularly to the brain and the central nervous system due to their inability to cross the blood/brain barrier. The delivery of pharmaceutically useful lipophilic substances is often challenging because of their low solubility in an aqueous environment. Though many advanced approaches have been developed for the delivery of these drugs, there are critical issues that need to be attended but not limited to thermodynamic instability, sedimentation, flocculation, administration of high dosage rates, side effects, and low absorption rates. Macro-emulsions are widely used to address some of the above issues; in particular, the size distribution and incompatibility of the components or excipients used in the emulsion, which makes it less efficient and tends to undergo separation before reaching the target site. Achieving enhanced bioavailability is a major problem faced while developing many delivery compositions, particularly for pharmaceutical compositions or agents that are poorly soluble in water. There is a need for improved compositions for lipophilic and partially lipophilic active substances that will promote stability in an aqueous environment and allow efficient delivery of such substances to a desired site of action.
Bioavailability depends on several factors, drug solubility in an aqueous environment and drug permeability through lipophilic membranes being important ones. Hence, it is important to improve the solubility and/or dissolution rate for lipophilic drugs. More than 40% of NCEs (new chemical entities) developed by the pharmaceutical industry recently are practically insoluble in water. These drugs are associated with slow drug absorption, leading to inadequate and variable bioavailability and mucosal toxicity. Micro-emulsions and nano emulsions offer several advantages, including improved drug solubility, enhanced bioavailability, protection of the drug from the environment, ease of manufacturing, and long shelf life.
When developing such compositions, it is to obtain systems with optimized drug loading and release properties, thermodynamic stability, long shelf-life, increased bioavailability and reduced toxicity. Though several micro and nanoemulsions of varied compositions have been described in the literature, they neither provide nanoparticle sized compositions having average particle size of less than 200 nm, nor do they provide compositions that are superior in at least one of the criteria i.e., higher drug loading, better in vivo performance, increased bioavailability, low viscosity, and rapid onset of action. These are achieved by the compositions of the present invention.
Many different strategies have been used in formulating micro-emulsions to make them suitable for the delivery of drugs requiring good solubility and stability. In patent applications no PCT/KR2002/001593 and PCT/US2003/010526, the use of oleic acid as the oil phase similar to the present invention for making a self-emulsifying drug delivery system was described. However, the composition contains high amounts of alcohol, which may cause irritancy to the absorption surface due to the drying effect. In addition, the drug loading and solubility described in the patent is much lower compared to the present invention.
PCT/GB2002/003005 discloses an emulsion comprising of an oil phase for delivery of benzodiazepine drug. The invention further limits the drug loading of the prototype benzodiazepine molecule (Midazolam) only to 10 mg/ml. However, it is well established in the literature that the drug loading capacity should be relatively high to allow for administration of the drug via different routes in order to be able to deliver the required therapeutic dose, as the dosing volume will be limited.
In CN 200810160956, a bicyclol submicroemulsion system having a particle size <500 nm and a drug loading capacity of 0.1 mg/ml has been described, whereas the current invention herein provides a highly stable composition having average particle size less than 150 nm and a high drug loading capacity.
Furthermore, U.S. Pat. No. 5,993,846 discloses oil-in-water emulsions having mucoadhesive properties which are primarily intended for administration of biologically active compounds to mucosal surfaces having particle diameter ranging from 10 nm to 600 nm. Further, the mucoadhesives prolong the residence time in situ. The invention disclosed herein describes compositions with a particle size between 10 to 150 nm and its immediate release. Another patent CA2347032 entitled ‘0/w emulsion comprising a hydroxylated oil’ describes an oil-in-water emulsion in which the oil phase comprises a hydroxylated oil preferably castor oil. This describes emulsions with particle size of 200 nm; the efficacy of the emulsions has not been established.
In CN101780037, a self emulsifying composition based on oliec acid is disclosed, however, oleic acid content is very high leading to greater viscocity and cause gelling problems upon the addition of water making it unstable unlike the instant invention.
Moreover, these compositions potentially are dependent on digestion prior to release of the drug. The drawbacks of this system include chemical instabilities of drugs and high surfactant concentrations in compositions. Early studies revealed that the selfemulsification process is specific to the nature of the oil/surfactant pair, the surfactant concentration and oil/surfactant ratio, the concentration and nature of co-surfactant and surfactant/co-surfactant ratio and the temperature at which self emulsification occurs. Due to presence of high surfactant and oil concentrations there may be chances of instabilities of drugs. Also the high content of surfactant in self emulsifying compositions irritates the GIT. This also causes less drug loading capabilty.
In Kumar et al. (2008) “Mucoadhesive nanoemulsion based intranasal drug delivery system of olanzapine for brain targeting” published on the Journal of Drug Targeting, contained 15% w/w Capmul MCM (medium-chain mono- and diglycerides) as oil, 35% Tween 80 (polysorbate 80) as a surfactant, 17.5% w/w of ethanol:polyethylene glycol 400 (1:1) mixture as co-surfactant, 32.5% water as aqueous phase and 0.5% chitosan as a muco-adhesive agent. However, this system has very low olanzapine loading i.e., only 8.5 mg/ml in the micro-emulsion was obtained. Furthermore, the aforementioned prior art has prolonged Tmax and achieves maximum concentration only after an hour in the case of brain and 2 hours in the case of blood plasma. This shows that the above said prior art fails in achieving the rapid onset of action when compared with the current invention.
In Patel et al entitled “Formulation and Evaluation of Microemulsions-Based Drug Delivery System for Intranasal Administration of Olanzapine”, Olanzapine micro-emulsion described comprises of a system with 4%> oleic acid content, 30% of surfactant:co-surfactant mix containing Labrasol®, Cremophor RH40, and Transcutol P in ratio of 1:1:0.3 and 0.5% polycarbophil as a mucoadhesive agent. The drug loading of the micro-emulsion was only 8 mg/ml. Another similar system described by Mukesh Kumar et al. in “Composition and Characterization of Nanoemulsion of Olanzapine for Intranasal Delivery” contains 15% w/w Capmul MCM (medium-chain mono- and diglycerides) as oil, 35% Tween 80 (polysorbate 80) as a surfactant, 17.5% w/w of ethanol:polyethylene glycol 400 (1:1) mixture as co-surfactant, 32.5% water as co-surfactant and 0.5% chitosan as a muco-adhesive agent. Olanzapine loading in micro-emulsion was only 8.5 mg/ml. Furthermore, these inventions are highly viscous and cause gelling problems upon the addition of water making it unstable unlike the instant invention. Furthermore the instant invention showed no separation or phase separation on centrifugation, unlike the prior art.
One such drug which requires immediate attention is 2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine, referred to by the International Non-proprietary Name (INN) olanzapine, is marketed as being useful for the treatment of schizophrenia, schizophreniform disorder, acute mania, bipolar disorder, mild anxiety states, and psychosis. U.S. Pat. No. 5,929,070A discloses that olanzapine is also useful in the control of pain associated with migraine. Presently, however, olanzapine must be administered orally in the form of tablets or capsules. This results in a substantial delay before the maximum concentration of active drug reaches the target site in the brain (long Tmax), with correspondingly slow onset of therapeutic effects.
It would be very desirable to have compositions for effective delivery of olanzapine and other therapeutic agents with a faster onset of action.
Accordingly, the present invention seeks to provide improved compositions with high therapeutic efficacy having an average particle size of less than 200 nm for pharmaceutical composition useful for the nasal, oral, intramuscular, ophthalmic, rectal or topical delivery of lipophilic or partially lipophilic drugs or as therapeutic, monitoring or diagnostic agents. Furthermore, the compositions address the aforementioned issues; particularly, they minimize drug degradation and loss, prevent harmful side-effects, increase drug bioavailability, improve solubility of some poorly soluble pharmaceutical components and provide a nano-sized low-viscose monophasic composition.